Combination therapy for treating cyclooxygenase-2 mediated diseases in patients at risk of thrombotic cardiovascular events

ABSTRACT

The present invention encompasses a method for treating a chronic cyclooxygenase-2 mediated disease or condition and reducing the risk of a thrombotic cardiovascular event in a human patient in need of such treatment and at risk of a thrombotic cardiovascular event comprising orally concomitantly or sequentially administering to said patient a cyclooxygenase-2 selective inhibitor in an amount effective to treat the cyclooxygenase-2 mediated disease or condition and nitric oxide releasing aspirin in an amount effective to reduce the risk of the thrombotic cardiovascular event while maintaining a high level of upper gastrointestinal safety and tolerability. The invention also encompasses a method for treating a chronic cyclooxygenase-2 mediated disease or condition and reducing the risk of a thrombotic cardiovascular event in a human patient in need of such treatment and at risk of a thrombotic cardiovascular event comprising orally concomitantly or sequentially administering to said patient a nitric oxide releasing-cyclooxygenase-2 selective inhibitor in an amount effective to treat the cyclooxygenase-2 mediated disease or condition and aspirin in an amount effective to reduce the risk of the thrombotic cardiovascular event while maintaining a high level of upper gastrointestinal safety and tolerability. Pharmaceutical compositions are also encompassed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase application under 35 U.S.C. §371 of PCT Application No. PCT/US03/14778, filed May 9, 2003, whichclaims priority under 35 U.S.C. 119 to U.S. No. 60/388,660, filed May10, 2002.

BACKGROUND OF THE INVENTION

Selective inhibitors of cyclooxygenase-2 are a sub-class of the class ofdrugs known as non-steroidal antiinflammatory drugs (NSAIDs). The NSAIDsare active in reducing the prostaglandin-induced pain and swellingassociated with the inflammation process but are also active inaffecting other prostaglandin-regulated processes not associated withthe inflammation process. Thus, use of high doses of most common NSAIDscan produce severe side effects, including life threatening ulcers, thatlimit their therapeutic potential. An alternative to NSAIDs is the useof corticosteroids, which have even more drastic side effects,especially when long term therapy is involved.

Previous NSAIDs have been found to prevent the production ofprostaglandin by inhibiting enzymes in the human arachidonicacid/prostaglandin pathway including the enzyme cyclooxygenase (COX).The recent discovery that there are two isoforms of the COX enzyme, thefirst, COX-1, being involved with physiological functions and thesecond, COX-2, being induced in inflamed tissue, has given rise to a newapproach. While conventional NSAIDs block both forms of the enzyme, theidentification of the inducible COX-2 enzyme associated withinflammation has provided a viable target of inhibition which moreeffectively reduces inflammation and produces fewer and less drasticside effects. Many compounds which have activity as COX-2 inhibitorshave been identified, including rofecoxib (VIOXX®), etoricoxib(ARCOXIA™), celecoxib (CELEBREX®) and valdecoxib (BEXTRA™), and muchresearch continues in this area.

Many patients with a chronic cyclooxygenase-2 mediated disease orcondition are elderly and thus are at increased risk for thromboticcardiovascular events, such as stroke, myocardial ischemia, myocardialinfarction, angina pectolis, transient ischemic attack (TIA; amaurosisfugax), reversible ischemic neurologic deficits, and any similarthrombotic event in any vascular bed (splanchnic, renal, aortic,peripheral, etc.). Moreover, there is evidence that patients withchronic inflammatory conditions, such as rheumatoid arthritis andsystemic lupus erythematosis are at increased risk for thromboticcardiovascular events. Thus, it is desirable that such patients receiveappropriate antiplatelet therapy, such as aspirin, to reduce their riskof such events. However, very recent information from studies of theCOX-2 selective inhibitors show that the incidence of gastric ulcerevents in patients receiving both low-dose aspirin and the COX-2selective inhibitor is similar to that seen with conventional NSAIDSthat inhibit both COX-1 and COX-2. Also, some conventional NSAIDS, suchas Naprosyn (naproxen sodium), when taken regularly, have been shown tohave significant antiplatelet activity as well as efficacy in treatingchronic cyclooxygenase-2 mediated diseases or conditions. Thus, themajor advantage that COX-2 specific inhibitors have over NSAIDS (used inisolation or in combination with aspirin) may be substantially orcompletely offset by the concomitant use of aspirin.

NO-releasing aspirin is a modified version of aspirin that is reportedto have improved antithrombtic effects as well as a reduced potentialfor gastrointestinal toxicity. See J. L. Wallace, et al., Nature reviewsDrug Discovery, vol. 1, pp. 375-382, May 2002.

In the current invention, nitric oxide releasing aspirin is administeredtogether with a cyclooxygenase-2 selective inhibitor or a nitric oxidereleasing-cycloxygenase-2 selective inhibitor is administered togetherwith aspirin leading to several advantages. First, the combinationreduces the risk of GI ulcers and bleeds (which is otherwiseparticularly increased when both a COX-2 inhibitor and aspirin areadministered on a daily basis) while providing substantial antiplateletefficacy. Second, the concomitant therapy provides symptom relief forthe chronic cyclooxygenase-2 mediated disease or condition, such aschronic pain or arthritis.

Thus, the invention provides for a clearly superior profile than thathitherto obtainable in that it provides efficacy in treating chroniccyclooxygenase-2 mediated diseases or conditions, effectively inhibitsplatelets thus reducing the risk of thrombotic cardiovascular events andat the same time reduces the risk of GI ulceration or bleeding relativeeither to conventional NSAIDS or separate administration of a COX-2inhibitor and low-dose daily aspirin, or than a NSAID plus aspirin.

SUMMARY OF THE INVENTION

The present invention encompasses a method for treating a chroniccyclooxygenase-2 mediated disease or condition and reducing the risk ofa thrombotic cardiovascular event in a human patient in need of suchtreatment and at risk of a thrombotic cardiovascular event comprisingorally concomitantly or sequentially administering to said patient acyclooxygenase-2 selective inhibitor in an amount effective to treat thecyclooxygenase-2 mediated disease or condition and nitric oxidereleasing aspirin in an amount effective to reduce the risk of thethrombotic cardiovascular event while maintaining a high level of uppergastrointestinal safety and tolerability. The invention also encompassesa method for treating a chronic cyclooxygenase-2 mediated disease orcondition and reducing the risk of a thrombotic cardiovascular event ina human patient in need of such treatment and at risk of a thromboticcardiovascular event comprising orally concomitantly or sequentiallyadministering to said patient a nitric oxide releasing-cyclooxygenase-2selective inhibitor in an amount effective to treat the cyclooxygenase-2mediated disease or condition and aspirin in an amount effective toreduce the risk of the thrombotic cardiovascular event while maintaininga high level of upper gastrointestinal safety and tolerability.Pharmaceutical compositions are also encompassed.

DETAILED DESCRIPTION OF THE INVENTION

The present invention encompasses a method for treating a chroniccyclooxygenase-2 mediated disease or condition and reducing the risk ofa thrombotic cardiovascular event in a human patient in need of suchtreatment and at risk of a thrombotic cardiovascular event comprisingorally concomitantly or sequentially administering to said patient acyclooxygenase-2 selective inhibitor in an amount effective to treat thecyclooxygenase-2 mediated disease or condition and nitric oxidereleasing aspirin in an amount effective to reduce the risk of thethrombotic cardiovascular event while maintaining a high level of uppergastrointestinal safety and tolerability. The invention also encompassesa method for treating a chronic cyclooxygenase-2 mediated disease orcondition and reducing the risk of a thrombotic cardiovascular event ina human patient in need of such treatment and at risk of a thromboticcardiovascular event comprising orally concomitantly or sequentiallyadministering to said patient a nitric oxide releasing-cyclooxygenase-2selective inhibitor in an amount effective to treat the cyclooxygenase-2mediated disease or condition and aspirin in an amount effective toreduce the risk of the thrombotic cardiovascular event while maintaininga high level of upper gastrointestinal safety and tolerability.

The term “treating a chronic cylcooxygenase-2 mediated disease orcondition” means treating or preventing any chronic disease or conditionthat is advantageously treated or prevented by inhibiting thecyclooxygenase-2 enzyme. The term includes the relief of pain, fever andinflammation of a variety of conditions including rheumatic fever,symptoms associated with influenza or other viral infections, commoncold, low back pain, neck pain, dysmenorrhea, headache, migraine,toothache, sprains and strains, myositis, neuralgia, synovitis,arthritis, including rheumatoid arthritis, degenerative joint diseases(osteoarthritis), gout, ankylosing spondylitis, bursitis, burns,injuries, and pain and inflammation following surgical procedures. Inaddition, such a compound may inhibit cellular neoplastictransformations and metastatic tumor growth and hence can be used in thetreatment and/or prevention of cancer. In addition, such a compound mayinhibit the onset or progression of Altzheimer's disease or cognitiveimpairment. The term also includes the treatment and/or prevention ofcyclooxygenase-mediated proliferative disorders such as may occur indiabetic retinopathy and tumor angiogenesis. The term “treating”encompasses not only treating a patient to relieve the patient of thesigns and symptoms of the disease or condition but also prophylacticallytreating an asymptomatic patient to prevent the onset or progression ofthe disease or condition.

A “thrombotic cardiovascular event” is defined as any sudden event of atype known to be caused by platelet aggregation, thrombosis, andsubsequent ischemic clinical events, including thrombotic orthromboembolic stroke, myocardial ischemia, myocardial infarction,angina pectoris, transient ischemic attack (TIA; amaurosis fugax),reversible ischemic neurologic deficits, and any similar thromboticevent in any vascular bed (splanchnic, renal, aortic, peripheral, etc.).

The term “patient in need of such treatment and at risk of a thromboticcardiovascular event” means a patient in need of both treatment for acyclooxygenase-2 mediated disease and also at risk of a thromboticcardiovascular event. One skilled in the art can diagnose a patient thatis in need of treatment for a cyclooxygenase-2 mediated disease orcondition and also at risk of suffering a thrombotic cardiovascularevent. For example, such a patient may be over the age of 50 withosteoarthritis and with a previous myocardial infarction. Other riskfactors for a thrombotic cardiovascular event include hypertension,hypercholesterolemia, diabetes mellitus, chronic renal impairment,smoking, and any prior personal or family history of such an event.Administration of the drug combination to the patient includes bothself-administration and administration to the patient by another person.

The terms “nitric oxide releasing-aspirin” and “NO-aspirin” mean amodified version of aspirin linked to a NO releasing moiety by means ofa linking group such as an ester linkage. Such compounds are known inthe art and disclosed, for example, in J. L. Wallace, et al., NatureReviews Drug Discovery, vol. 1, pp. 375-382, May 2002, which is herebyincorporated by reference in its entirety. See the compound referredtherein as NCX4016. Other examples of nitric oxide releasing NSAIDs arewell known in the art and are disclosed, for example, in the followingpatents and published applications which are hereby incorporated byreference in their entirety: U.S. Pat. No. 6,323,234, issued on Nov. 27,2001; U.S. Pat. No. 6,297,260, issued on Oct. 2, 2001; U.S. Pat. No.6,143,734, issued on Nov. 7, 2000; U.S. Pat. No. 6,083,515, issued onJul. 4, 2000; U.S. Pat. No. 6,057,347, issued on May 2, 2000; U.S. Pat.No. 6,048,858, issued on Apr. 11, 2000; U.S. Pat. No. 6,043,233, issuedon Mar. 28, 2000; U.S. Pat. No. 6,043,232, issued Mar. 28, 2000; U.S.Pat. No. 5,780,495, issued Jul. 14, 1998; U.S. Pat. No. 5,703,073,issued Dec. 30, 1997; U.S. Pat. No. 5,700,947, issued Dec. 23, 1997;U.S. Pat. No. 5,621,000, issued Apr. 15, 1997; WO 00/25776, published onMay 11, 2000; WO 96/32946, published on Oct. 24, 1996; and WO 95/09831,published on Apr. 13, 1995. See also, Bandarage, et al., J. Med. Chem.,vol. 43, pp. 4005-4016, 2000; Wallace, et al., Drug DevelopmentResearch, vol. 42, pp. 144-149, 1997; Wallace, et al., Gastroenterology,vol. 107, pp. 173-179, 1994; and Wallace, et al., European Journal ofPharmacology, vol. 257, pp. 249-255, 1994, all of which are herebyincorporated by reference in their entirety.

The terms “inhibitor of cyclooxygenase-2”, “cyclooxygenase-2 selectiveinhibitor” and “COX-2 inhibitor” as used herein embrace compounds whichselectively inhibit cyclooxygenase-2 over cyclooxygenase-1. Employingthe human whole blood COX-1 assay and the human whole blood COX-2 assaydescribed in C. Brideau et al, Inflamm. Res. 45: 68-74 (1996), hereinincorporated by reference, preferably, the compounds have acyclooxygenase-2 IC₅₀ of less than about 2 μM in the human whole bloodCOX-2 assay, yet have a cyclooxygenase-1 IC₅₀ of greater than about 5 μMin the human whole blood COX-1 assay. Also preferably, the compoundshave a selectivity ratio of cyclooxygenase-2 inhibition overcyclooxygenase-1 inhibition of at least 10, and more preferably of atleast 40. The resulting selectivity may indicate an ability to reducethe incidence of common NSAID-induced side effects, especially erosionsand ulceration of the upper gastrointestinal mucosa.

Examples of cyclooxygenase-2 selective inhibitors include rofecoxib(VIOXX®, see U.S. Pat. No. 5,474,995, hereby incorporated by referencein its entirety), etoricoxib (ARCOXA™ see U.S. Pat. No. 5,861,419,hereby incorporated by reference in its entirety), celecoxib (CELEBREX®,see U.S. Pat. No. 5,466,823, hereby incorporated by reference in itsentirety), valdecoxib (see U.S. Pat. No. 6,633,272, hereby incorporatedby reference in its entirety), parecoxib (see U.S. Pat. No. 5,932,598,hereby incorporated by reference in its entirety), COX-189 (Novartis),BMS347070 (Bristol Myers Squibb), tiracoxib or JTE522 (Japan Tobacco),ABT963 (Abbott), CS502 (Sankyo) and GW406381 (GlaxoSmithKline).

The terms “nitric oxide releasing-cyclooxygenase-2 selective inhibitor,”“NO-cyclooxygenase-2 selective inhibitor,” “nitric oxide releasing-COX-2inhibitor” and “NO-COX-2 inhibitor” mean a modified version of acycloxygenase-2 selective inhibitor as defined above linked to a NOreleasing moiety by means of a linking group such as an ester linkage.Examples of such compounds are known in the art and disclosed, forexample, in WO01/45703, published on Jun. 28, 2001, which is herebyincorporated by reference in its entirety.

The term “amounts that are effective to treat” is intended to mean thatamount of a drug or pharmaceutical agent that will elicit the biologicalor medical response of a tissue, a system, animal or human that is beingsought by a researcher, veterinarian, medical doctor or other clinician.The term also encompasses the amount of a pharmaceutical drug that willprevent or reduce the risk of occurrence of the biological or medicalevent that is sought to be prevented in a tissue, a system, animal orhuman by a researcher, veterinarian, medical doctor or other clinician.The inhibitor of cyclooxygenase-2 may be administered at a dosage levelup to conventional dosage levels for NSAIDs. Suitable dosage levels willdepend upon the antiinflammatory effect of the chosen inhibitor ofcyclooxygenase-2, but typically suitable levels will be about 0.001 to50 mg/kg per day, preferably 0.005 to 30 mg/kg per day, and especially0.05 to 10 mg/kg per day. The compound may be administered on a regimenof once or twice per day.

The term “amount effective to reduce the risk of means the amount of apharmaceutical drug that will prevent or reduce the risk of occurrenceof the biological or medical event that is sought to be prevented in atissue, a system, animal or human by a researcher, veterinarian, medicaldoctor or other clinician. Aspirin is administered at a dose of about 30mg to about 1 g once daily, preferably at a dose of about 80 mg to about650 mg.

The term “concomitantly administering” means administering the agentssubstantially concurrently. The term “concomitantly administering”encompasses not only administering the two agents in a singlepharmaceutical dosage form but also the administration of each activeagent in its own separate pharmaceutical dosage formulation. Whereseparate dosage formulations are used, the agents can be administered atessentially the same time, i.e., concurrently.

The term “sequentially administering” means administering the agents atseparately staggered times. Thus, agents can be sequentiallyadministered such that the beneficial pharmaceutical effect ofNO-aspirin and the COX-2 inhibitor or aspirin and the NO-COX-2 inhibitorare realized by the patient at substantially the same time. Thus, forexample, if a COX-2 selective inhibitor and NO releasing aspirin areboth administered on a once a day basis, the interval of separationbetween sequential administration of the two agents can be up to twelvehours apart.

The invention encompasses a method for treating a chroniccyclooxygenase-2 mediated disease or condition and reducing the risk ofa thrombotic cardiovascular event in a human patient in need of suchtreatment and at risk of a thrombotic cardiovascular event comprisingorally concomitantly or sequentially administering to said patient acyclooxygenase-2 selective inhibitor in an amount effective to treat thecyclooxygenase-2 mediated disease or condition and nitric oxidereleasing aspirin in an amount effective to reduce the risk of thethrombotic cardiovascular event. Within this embodiment is encompassedthe above method wherein the cyclooxygenase-2 selective inhibitor isselected from the group consisting of: rofecoxib, etoricoxib, celecoxib,valdecoxib, COX-189, BMS347070, tiracoxib, ABT963, CS502 and GW406381.Also, within this embodiment is encompassed the above method wherein thecyclooxygenase-2 selective inhibitor is rofecoxib. Also, within thisembodiment is encompassed the above method wherein rofecoxib isadministered on a once or twice daily basis at a dose of about 12.5 mgor about 25 mg. Also, within this embodiment is encompassed the abovemethod wherein rofecoxib is administered on a once daily basis. Also,within this embodiment is encompassed the above method wherein thecyclooxygenase-2 selective inhibitor is etoricoxib. Also, within thisembodiment is encompassed the above method wherein etoricoxib isadministered on a once or twice daily basis at a dose of about 60 mg,about 90 mg or about 120 mg. Also, within this embodiment is encompassedthe above method wherein the cyclooxygenase-2 selective inhibitor iscelecoxib. Also, within this embodiment is encompassed the above methodwherein wherein celecoxib is administered on a once or twice daily basisat a dose of about 100 mg or about 200 mg or 400 mg. Also, within thisembodiment is encompassed the above method wherein the cyclooxygenase-2selective inhibitor is valdecoxib. Also, within this embodiment isencompassed the above method wherein valdecoxib is administered on aonce or twice daily basis at a dose of about 10 mg or about 20 mg. Also,within this embodiment is encompassed the above method wherein whereinthe cyclooxygenase-2 selective inhibitor is administered orally on aonce daily basis. Also, within this embodiment is encompassed the abovemethod wherein wherein the cyclooxygenase-2 selective inhibitor isadministered orally on a twice daily basis.

Another embodiment of the invention encompasses the above method whereinthe cyclooxygenase-2 selective mediated disease or condition isosteoarthritis. Another embodiment of the invention encompasses theabove method wherein the cyclooxygenase-2 selective mediated disease orcondition is rheumatoid arthritis. Another embodiment of the inventionencompasses the above method wherein the cyclooxygenase-2 selectivemediated disease or condition is chronic pain.

The invention also encompasses the above method wherein nitric oxidereleasing aspirin is administered at a dose of about 30 mg to about 1 g.Another embodiment of the invention encompasses the above method whereinnitric oxide releasing aspirin is administered at a dose of about 80 toabout 650 mg. Another embodiment of the invention encompasses the abovemethod wherein nitric oxide releasing aspirin is administered at a doseof about 81 mg. Another embodiment of the invention encompasses theabove method wherein nitric oxide releasing aspirin is administered at adose of about 325 mg. Another embodiment of the invention encompassesthe above method wherein aspirin is orally administered once daily.

The invention also encompasses a method for treating a chroniccyclooxygenase-2 mediated disease or condition and reducing the risk ofa thrombotic cardiovascular event in a human patient in need of suchtreatment and at risk of a thrombotic cardiovascular event comprisingorally concomitantly or sequentially administering to said patient anitric oxide releasing-cyclooxygenase-2 selective inhibitor in an amounteffective to treat the cyclooxygenase-2 mediated disease or conditionand aspirin in an amount effective to reduce the risk of the thromboticcardiovascular event. Also within this embodiment is encompassed theabove method wherein the nitric oxide releasing-cyclooxygenase-2selective inhibitor is administered orally on a once daily basis. Alsowithin this embodiment is encompassed the above method wherein thenitric oxide releasing-cyclooxygenase-2 selective inhibitor isadministered orally on a twice daily basis.

Another embodiment of the invention encompasses the above method whereinthe cyclooxygenase-2 selective mediated disease or condition isosteoarthritis. Another embodiment of the invention encompasses theabove method wherein the cyclooxygenase-2 selective mediated disease orcondition is rheumatoid arthritis. Another embodiment of the inventionencompasses the above method wherein the cyclooxygenase-2 selectivemediated disease or condition is chronic pain.

The invention also encompasses the above method wherein aspirin isadministered at a dose of about 30 mg to about 1 g. Another embodimentof the invention encompasses the above method wherein aspirin isadministered at a dose of about 80 to about 650 mg. Another embodimentof the invention encompasses the above method wherein aspirin isadministered at a dose of about 81 mg. Another embodiment of theinvention encompasses the above method wherein aspirin is administeredat a dose of about 325 mg. Another embodiment of the inventionencompasses the above method wherein aspirin is orally administered oncedaily.

The invention also encompasses a pharmaceutical composition comprising acyclooxygenase-2 selective inhibitor and nitric oxide releasing aspirinin combination with a pharmaceutically acceptable carrier. Within thisembodiment is encompassed the pharmaceutical composition wherein thenitric oxide releasing aspirin is present in an amount ranging fromabout 80 to about 650 mg. Also within this embodiment is encompassed thepharmaceutical composition wherein the cyclooxygenase-2 selectiveinhibitor is rofecoxib. Also within this embodiment is encompassed thepharmaceutical composition wherein rofecoxib is present in an amount ofabout 12.5 mg or about 25 mg. Also within this embodiment is encompassedthe pharmaceutical composition wherein the cyclooxygenase-2 selectiveinhibitor is etoricoxib. Also within this embodiment is encompassed thepharmaceutical composition wherein etoricoxib is present at a dose ofabout 60 mg, about 90 mg or about 120 mg.

The invention also encompasses a pharmaceutical composition comprising anitric oxide releasing-cyclooxygenase-2 selective inhibitor and aspirinin combination with a pharmaceutically acceptable carrier. Within thisembodiment is encompassed the pharmaceutical composition wherein aspirinis present in an amount ranging from about 80 to about 650 mg.

The present invention also encompasses a method for treating a chroniccyclooxygenase-2 mediated disease or condition and reducing the combinedrisk of death and nonfatal stroke in a human patient who has hadischemic stroke of transient ischemia of the brain due to fibrinplatelet emboli and also in need of treatment for a chroniccyclooxygenase-2 mediated disease comprising:

-   -   1) orally concomitantly or sequentially administering to said        patient a cyclooxygenase-2 selective inhibitor in an amount        effective to treat the cyclooxygenase-2 mediated disease or        condition and nitric oxide releasing aspirin in an amount        effective to reduce the combined risk of death and nonfatal        stroke, or    -   2) orally concomitantly or sequentially administering to said        patient a nitric oxide releasing-cyclooxygenase-2 selective        inhibitor in an amount effective to treat the cyclooxygenase-2        mediated disease or condition and aspirin in an amount effective        to reduce the combined risk of death and nonfatal stroke in a        human patient who has had ischemic stroke of transient ischemia        of the brain due to fibrin platelet emboli.

The present invention also encompasses a method for treating a chroniccyclooxygenase-2 mediated disease or condition and reducing the combinedrisk of death and nonfatal myocardial infarction in a human patient witha previous myocardial infarction or unstable angina pectoris and also inneed of treatment for a chronic cyclooxygenase-2 mediated diseasecomprising:

-   -   1) orally concomitantly or sequentially administering to said        patient a cyclooxygenase-2 selective inhibitor in an amount        effective to treat the cyclooxygenase-2 mediated disease or        condition and nitric oxide releasing aspirin in an amount        effective to reduce the combined risk of death and nonfatal        myocardial infarction, or    -   2) orally concomitantly or sequentially administering to said        patient a nitric oxide releasing-cyclooxygenase-2 selective        inhibitor in an amount effective to treat the cyclooxygenase-2        mediated disease or condition and aspirin in an amount effective        to reduce the combined risk of death and nonfatal myocardial        infarction.

The present invention also encompasses a method for treating a chroniccyclooxygenase-2 mediated disease or condition and reducing the combinedrisk of death and nonfatal myocardial infarction in a human patient withchronic stable angina pectoris and also in need of treatment for achronic cyclooxygenase-2 mediated disease comprising

-   -   1) orally concomitantly or sequentially administering to said        patient a cyclooxygenase-2 selective inhibitor in an amount        effective to treat the cyclooxygenase-2 mediated disease or        condition and nitric oxide releasing aspirin in an amount        effective to reduce the combined risk of death and nonfatal        myocardial infarction, or    -   2) orally concomitantly or sequentially administering to said        patient a nitric oxide releasing-cyclooxygenase-2 selective        inhibitor in an amount effective to treat the cyclooxygenase-2        mediated disease or condition and aspirin in an amount effective        to reduce the combined risk of death and nonfatal myocardial        infarction.

For purposes of this specification, references to the compounds of usein this invention are meant to also include the pharmaceuticallyacceptable salts.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases including inorganicbases and organic bases. Salts derived from inorganic bases includealuminum, ammonium, calcium, copper, ferric, ferrous, lithium,magnesium, manganic salts, manganous, potassium, sodium, zinc, and thelike. Particularly preferred are the ammonium, calcium, magnesium,potassium, and sodium salts. Salts derived from pharmaceuticallyacceptable organic non-toxic bases include salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, and basic ion exchange resins, suchas arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine,diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine,glucamine, glucosarnine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

The compounds of use in this invention may have one or more chiralcenters and the present compounds may occur as racemates, racemicmixtures and as individual diasteriomers or enantiomers with all suchisomeric forms and mixtures thereof being included within the scope ofthis invention. Furthermore, some of the crystalline forms for compoundsof the present invention may exist as polymorphs and as such areintended to be included in the present invention. In addition, some ofthe compounds of the instant invention may form solvates with water orcommon organic solvents. Such solvates and hydrates, as well asanhydrous compositions, are encompassed within the scope of thisinvention. Some of the compounds described herein may contain olefinicdouble bonds, and unless specified otherwise, are meant to include bothE and Z geometric isomers.

The COX-2 inhibitors or NO-COX-2 inhibitors that may be used with thisinvention encompass all pharmaceutically acceptable salt forms of thecompounds. Examples of such salt forms include but are not limited tosalts derived from inorganic bases including aluminum, ammonium,calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts,manganous, potassium, sodium, zinc, and the like. Particularly preferredare the ammonium, calcium, magnesium, potassium, and sodium salts. Saltsderived from pharmaceutically acceptable organic non-toxic bases includesalts of primary, secondary, and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines, andbasic ion exchange resins, such as arginine, betaine, caffeine, choline,N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosarnine,histidine, hydrabamine, isopropylamine, lysine, methylglucamine,morpholine, piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine,tromethamine, and the like.

When treating a patient following the methods of the present invention,the combination may be administered on the same day. Thus, the instantpharmaceutical combination includes administration of a singlepharmaceutical dosage formulation which contains both NO-aspirin and theCOX-2 inhibitor or aspirin and the NO-COX-2 inhibitor, as well asadministration of each active agent in its own separate pharmaceuticaldosage formulation. Where separate dosage formulations are used, theagents can be administered at essentially the same time, i.e.,concurrently, or at separately staggered times, i.e., sequentially. Theinstant pharmaceutical combination is understood to include all theseregimens. Administration in these various ways are suitable for thepresent invention as long as the beneficial pharmaceutical effect ofNO-aspirin and the COX-2 inhibitor or aspirin and the NO-COX-2 inhibitorare realized by the patient at substantially the same time. The dosageregimen utilizing the instant combination therapy is selected inaccordance with a variety of factors including type, species, age,weight, sex and medical condition of the patient; the severity of thecondition to be treated; the route of administration; the renal andhepatic function of the patient; and the particular compound or salt orester thereof employed.

In the methods of the present invention, the active agents are typicallyadministered in admixture with suitable pharmaceutical diluents,excipients or carriers (collectively referred to herein as “carrier”materials) suitably selected with respect to the intended form ofadministration, that is, oral tablets, capsules, elixirs, syrups and thelike, and consistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with a non-toxic,pharmaceutically acceptable, inert carrier such as lactose, starch,sucrose, glucose, modified sugars, modified starches, methyl celluloseand its derivatives, dicalcium phosphate, calcium sulfate, mannitol,sorbitol and other reducing and non-reducing sugars, magnesium stearate,steric acid, sodium stearyl fumarate, glyceryl behenate, calciumstearate and the like. For oral administration in liquid form, the drugcomponents can be combined with non-toxic, pharmaceutically acceptableinert carrier such as ethanol, glycerol, water and the like. Moreover,when desired or necessary, suitable binders, lubricants, disintegratingagents and coloring and flavoring agents can also be incorporated intothe mixture. Stabilizing agents such as antioxidants (BHA, BHT, propylgallate, sodium ascorbate, citric acid) can also be added to stabilizethe dosage forms. Other suitable components include gelatin, sweeteners,natural and synthetic gums such as acacia, tragacanth or alginates,carboxymethylcellulose, polyethylene glycol, waxes and the like.

The active drugs can also be administered in the form of liposomedelivery systems, such as small unilamellar vesicles, large unilamellarvesicles and multilamellar vesicles. Liposomes can be formed from avariety of phospholipids, such as cholesterol, stearylamine orphosphatidylcholines.

Active drug may also be delivered by the use of monoclonal antibodies asindividual carriers to which the compound molecules are coupled. Activedrug may also be coupled with soluble polymers as targetable drugcarriers. Such polymers can include polyvinyl-pyrrolidone, pyrancopolymer, polyhydroxy-propyl-methacrylamide-phenol,polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, active drug may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example, polylactic acid, polyglycolicacid, copolymers of polylactic and polyglycolic acid, polyepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates and cross linked or amphipathicblock copolymers of hydrogels.

The instant invention also encompasses a process for preparing apharmaceutical composition comprising combining nitric oxidereleasing-aspirin and the COX-2 inhibitor with a pharmaceuticallyacceptable carrier, as well as the pharmaceutical composition which ismade by combining nitric oxide releasing-aspirin and the COX-2 inhibitorwith a pharmaceutically acceptable carrier. The instant invention alsoencompasses a process for preparing a pharmaceutical compositioncomprising combining aspirin and the nitric oxide releasing-COX-2inhibitor with a pharmaceutically acceptable carrier, as well as thepharmaceutical composition which is made by combining aspirin and thenitric oxide releasing-COX-2 inhibitor with a pharmaceuticallyacceptable carrier.

A therapeutically effective amount of nitric oxide releasing-aspirin anda COX-2 inhibitor can be used together for the preparation of amedicament useful for treating or preventing the disease or conditionsherein. For example, the medicament may be comprised of a COX-2inhibitor in combination with about 30 mg to 1 g of nitric oxidereleasing-aspirin, or more particularly about 80 mg to about 650 mg ofnitric oxide releasing-aspirin. A therapeutically effective amount ofaspirin and a nitric oxide releasing-COX-2 inhibitor can be usedtogether for the preparation of a medicament useful for treating orpreventing the disease or conditions herein. For example, the medicamentmay be comprised of a nitric oxide releasing-COX-2 inhibitor incombination with about 30 mg to 1 g of aspirin, or more particularlyabout 80 mg to about 650 mg of aspirin.

The instant invention also encompasses the use of nitric oxidereleasing-aspirin for the preparation of a medicament for the combineduse with a cyclooxygenase-2 inhibitor for use as provided by the presentinvention; and the use of a cyclooxygenase-2 inhibitor for thepreparation of a medicament for the combined use with nitric oxidereleasing-aspirin for use as provided by the present invention.

The instant invention also encompasses the use of aspirin for thepreparation of a medicament for the combined use with a nitric oxidereleasing-cyclooxygenase-2 inhibitor for use as provided by the presentinvention; and the use of a nitric oxide releasing-cyclooxygenase-2inhibitor for the preparation of a medicament for the combined use withaspirin for use as provided by the present invention.

1-21. (canceled)
 22. A method for treating a chronic cyclooxygenase-2mediated disease or condition and reducing the risk of a thromboticcardiovascular event in a human patient in need of such treatment and atrisk of a thrombotic cardiovascular event comprising orallyconcomitantly or sequentially administering to said patient a nitricoxide releasing-cyclooxygenase-2 selective inhibitor in an amounteffective to treat the cyclooxygenase-2 mediated disease or conditionand aspirin in an amount effective to reduce the risk of the thromboticcardiovascular event.
 23. The method according to claim 22 wherein thenitric oxide releasing-cyclooxygenase-2 selective inhibitor isadministered orally on a once daily basis.
 24. The method according toclaim 22 wherein the nitric oxide releasing-cyclooxygenase-2 selectiveinhibitor is administered orally on a twice daily basis.
 25. The methodaccording to claim 22 wherein the cyclooxygenase-2 selective mediateddisease or condition is osteoarthritis.
 26. The method according toclaim 22 wherein the cyclooxygenase-2 selective mediated disease orcondition is rheumatoid arthritis.
 27. The method according to claim 22wherein the cyclooxygenase-2 selective mediated disease or condition ischronic pain.
 28. The method according to claim 22 wherein aspirin isadministered at a dose of about 30 mg to about 1 g.
 29. The methodaccording to claim 28 wherein aspirin is administered at a dose of about80 to about 650 mg.
 30. The method according to claim 29 wherein aspirinis administered at a dose of about 81 mg.
 31. The method according toclaim 29 wherein aspirin is administered at a dose of about 325 mg. 32.The method according to claim 22 wherein aspirin is orally administeredonce daily. 33-38. (canceled)
 39. A pharmaceutical compositioncomprising a nitric oxide releasing-cyclooxygenase-2 selective inhibitorand aspirin in combination with a pharmaceutically acceptable carrier.40. The pharmaceutical composition according to claim 39 wherein aspirinis present in an amount ranging from about 80 to about 650 mg.